Original Paper
Cell Death and Differentiation (2006) 13, 446–453. doi:10.1038/sj.cdd.4401759; published online 16 September 2005
Valproic acid induces extracellular signal-regulated kinase 1/2 activation and inhibits apoptosis in endothelial cells
Edited by G Ciliberto
M Michaelis1, T Suhan1, U R Michaelis2, K Beek1, F Rothweiler1, L Tausch3, O Werz3, D Eikel4, M Zörnig5, H Nau4, I Fleming2, H W Doerr1 and J Cinatl Jr1
- 1Institut für Medizinische Virologie, Klinikum der J.W. Goethe-Universität, Paul Ehrlich-Str. 40, 60596 Frankfurt am Main, Germany
- 2Institut für Kardiovaskuläre Physiologie, Klinikum der J.W. Goethe-Universität, Theodor-Stern-Kai, 7, 60590 Frankfurt am Main, Germany
- 3Institut für Pharmazeutische Chemie, J.W. Goethe-Universität, Marie-Curie-Str. 9, 60439 Frankfurt am Main, Germany
- 4Zentrum für Lebensmittelwissenschaften, Zentrum für systemische Neurowissenschaften Hannover, Institut für Lebensmitteltoxikologie und Chemische Analytik, Tierärztliche Hochschule Hannover, Bischofsholer Damm 15, 30173 Hannover, Germany
- 5Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus, Paul Ehrlich-Str. 42-44, 60596 Frankfurt am Main, Germany
Correspondence: J Cinatl, Institut für Medizinische Virologie, Klinikum der J.W. Goethe-Universität, Paul Ehrlich-Str. 40, 60596 Frankfurt am Main, Germany. Tel: +49-69-6301-6409; Fax: +49-69-6301-4302; E-mail: Cinatl@em.uni-frankfurt.de
Received 24 March 2005; Revised 10 June 2005; Accepted 20 July 2005; Published online 16 September 2005.
Abstract
The histone deacetylase (HDAC) inhibitor valproic acid (VPA) was recently shown to inhibit angiogenesis, but displays no toxicity in endothelial cells. Here, we demonstrate that VPA increases extracellular signal-regulated kinase 1/2 (ERK 1/2) phosphorylation in human umbilical vein endothelial cells (HUVEC). The investigation of structurally modified VPA derivatives revealed that the induction of ERK 1/2 phosphorylation is not correlated to HDAC inhibition. PD98059, a pharmacological inhibitor of the mitogen-activated protein kinase kinase 1/2, prevented the VPA-induced ERK 1/2 phosphorylation. In endothelial cells, ERK 1/2 phosphorylation is known to promote cell survival and angiogenesis. Our results showed that VPA-induced ERK 1/2 phosphorylation in turn causes phosphorylation of the antiapoptotic protein Bcl-2 and inhibits serum starvation-induced HUVEC apoptosis and cytochrome c release from the mitochondria. Moreover, the combination of VPA with PD98059 synergistically inhibited angiogenesis in vitro and in vivo.
Keywords:
valproic acid, endothelial cell, apoptosis, angiogenesis, ERK
Abbreviations:
bFGF, basic fibroblast growth factor; CAM, chick chorioallantoic membrane; eNOS, endothelial nitric oxide synthase; ERK 1/2, extracellular signal-regulated kinases 1/2; FCS, foetal calf serum; HDAC, histone deacetylases; HDACI, histone deacetylase inhibitor; HUVEC, human umbilical vein endothelial cells; IMDM, Iscove's modified Dulbecco's medium; MEK 1/2, mitogen-activated protein kinase kinase 1/2; TSA, trichostatin A
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